The specific aims of the proposed research are to address some of the critical questions about trdive dyskinesia (TD) and acute extrapyramidal syndromes (EPS) induced by antipsychotic drugs, by extending through placebo-controlled trials the earlier investigations in non-human primates. The central theme of this research is to characterize the preexisting individual vulnerability to alterations in dopaninergic (DA) function and to correlate differences between individual subjects, drug dose and blood levels, and temporal variables with the propensity to develop drug-induced dyskinesias. These associations will be assessed by evaluating the effects of different DA agonists ( apomorphine, d-amphetamine, and 2 chemically different ergots, bromocriptine and pergolide) and an antagonist (haloperidol) on locomotor activity, stereotypic behavior, buccolinguo-masticatory movements, arousal, and eye blinking rates. During the subsequent chronic haloperidol treatment, the development of acute EPS and the interaction between acutely administered DA agonists and chronic antagonist treatment will be studied to chart the evolution of "latent" hypersensitivity to the clinically obvious TD. Among the monkeys which develop TD, the natural history of theis syndrome will be obnserved, and the capacity of different classes of antipsychotic drugs to suppress and then aggravate the symptoms will be evaluated. Finally, correlation betwen the initial individual sensitivity to DA agonists and antagonists, the response to chronic antagonist treatment, and the eventual development of TD will be made. The proposed studies in a non-human primate homologous model of antipsychotic druginduced dyskinesias will provide both clinically relevant and heuristic data that are not available from clinical psychiatry because ethical constraints prohibit naturalistic studies of serious side effects. Evaluation the relationships between initial individual differences, drug blood levels, acute EPS, and the natural history of TD will be an important addition to our current understanding of these syndromes, and may lead to methods for identifying patients who are predisposed to drug-induced dyskinesisa.